Sphingosine 1-phosphate (S1P) is derived from sphingosine, which provides the backbone to all sphingolipids. Phosphorylation of sphingosine, a metabolite of the pro-apoptotic lipid ceramide, to S1P, is mediated by lipid kinases called sphingosine kinases (SphK). There are two SphK isoenzymes: SphK1 or SphK2. SIP may be reversibly deactivated through dephosphorylation by several phosphatases or irreversibly deactivated by S1P lyase. S1P is produced intracellularly in organelles and the plasma membrane and then secreted. The newly generated S1P is then secreted and is bound extensively by albumin and other plasma proteins. This provides a stable reservoir in extracellular fluids, presumably at higher total concentrations than in tissues, and rapid delivery to cell surface receptors. S1P, via its five cognate G-protein coupled receptors (GPCRs), S1P1-5 Rs, regulates diverse biological functions, including inflammatory responses, cell proliferation, apoptosis, cell migration, lymphocyte trafficking and cell senescence. Thus, coordinated activities of biosynthetic and biodegradative enzymes help maintain and regulate concentrations of S1P in the range required for physiological activities.
S1P has been shown to be an important mediator of angiogenesis and tumorigenesis. One way to modulate S1P levels is to target SphK, and thereby affect biosynthesis of S1P. SphK1 has been shown to stimulate proliferation in vitro, and is tumorigenic in vivo. It also imparts resistance to radiotherapy and chemotherapy and is elevated in some solid tumors. SphK1 inhibitors have been shown to have anti-cancer effects in vivo. These effects have been attributed to the inhibition of formation of S1P. Further, a monoclonal antibody against S1P reduces progression of or eliminates tumors in murine xenograft and allograft models. Thus, lowering levels of S1P by inhibiting SphK or by an S1P-specific antibody has anti-tumorigenic effects.
Since many, if not all effects of S1P are mediated by five GPCRs, an alternative approach to cancer therapy may be inhibition of S1P receptors. Of the five known S1P receptors, S1P1R has been shown to play an important role in vascular permeability and S1P1R knock-out mice have an embryonic lethal phenotype. Furthermore, there is increasing evidence for cross-talk between S1P1R and other growth factor receptors such as PDGFR. Thus, S1P1R receptor antagonists have the potential to offer clinical benefit as anti-cancer therapeutics.
Antimicrotubule drugs such as taxanes, vinca alkaloids and epothilones are a major category of anticancer agents (Rowinsky, E. K., and Tolcher, A. W., Antimicrotubule agents. In: V. T. Devita, Jr., and S. Hellman, and S. A. Rosenberg (eds.) Cancer Principles and Practice, Ed. 6, pp 431-452. Philadelphia: Lippincott Williams and Wilkins, 2001). Antimicrotubule drugs work by interfering with the function of cellular microtubules, particularly the mitotic spindle. The disruption of normal spindle function leads to apoptotic cell death.
Taxanes are antimicrotubule agents and are part of a class of compounds called diterpenes. Compounds of this type are produced by and originally isolated from plants of the genus Taxus. For example, paclitaxel was originally isolated from the bark of the Pacific yew tree Taxus brevivolia. Recently, taxanes and their intermediates were isolated from other plant species as well, (Ottaggio et al., J. Nat. Prod. 2008, 71:58-60). Presently, most of the drug used for clinical use is produced by a semisynthesis (Holton et al., in Taxol Science and applications; Suffness, M., Ed.; CRC Press: Boca Raton, 1995; pp 97-121), starting from a natural precursor, 10-deadetylbaddatin III, that is more redily available from the needles of yew species as a renewable source (Hook, I. et al., Phytochemistry 1999, 52:1041-1045, van Rocendaal, E. L. M., et al., Phytochemistry 2000, 53:383-389).
The taxanes are a group of drugs that are used in the treatment of cancer. Taxanes have a unique way of preventing the growth of cancer cells, they are anti-mitotic and anti-microtubule agents. Taxanes are microtubule stabilizing agents and interfere with microtubule breakdown which results in cessation of cancer cell growth and division. Taxanes have been used in the treatment of a wide variety of cancers.
Vinca alkaloids are antimicrotubule agents and are part of a class of compounds called plant alkaloids. Vinca compounds of this type are produced and were originally isolated from plants of the genus Vinca and specifically from Vinca rosea. Unlike the taxanes which are microtubule stabilizing agents, vinca alkaloids are microtubule destabilizing agents that cause microtubule depolymerization and inhibit mitotic progression and ultimately result in apoptotic cell death (Perez, E. A., Molecular Cancer Therapeutics 2009, 8:2086-2095). Vinca alkaloids have also been used in the treatment of a wide variety of cancers.